This application is a 371 of PCT/JP00/01487 filed Mar. 10, 2000.
The present invention relates to an agent for treatment of arthritic disease such as rheumatoid arthritis.
Arthritic diseases including diseases such as rheumatoid arthritis, osteoarthritis and traumatic arthritis are inflammatory diseases that causes destruction of cartilage and bone mediated by inflammation of joint synovial membrane. Vascular neogenesis, lymphocyte invasion and proliferation and activation of synovial cells are observed in the inflamed synovial membrane. Activated synovial cells produce chemical mediators such as cytokines, prostaglandins and matrix metalloproteinases, and are considered to cause destruction of cartilage and bone (Harris, E.D., New England Journal of Medicine, Vol. 322, p. 1277-1289 (1990); and, Cash, J.M., et al., New England Journal of Medicine, Vol. 330, p. 1368-1375 (1994)).
Hyaluronic acid in the form of a sodium salt is known to be effective for treatment or arthritic disease (reference: Yamamoto, M. et al. xe2x80x9cClinical Evaluation of High Molecular Sodium Hyaluronate (NRD) on Osteoarthritis of the Knee.xe2x80x9d Jpn Pharmacol Ther Vol. 21, No 3, (1993)). In addition, zinc is known to be effective for treatment or arthritis (A. Frigo, et al., xe2x80x9cCopper and Zinc in Inflammationxe2x80x9d, Inflammation and drug therapy series, Vol. IV, Kluwer Academic Publishers, p. 133-142 (1989)).
However, although hyaluronic acid (typically in the form of a sodium salt) is known for treatment of arthritic diseases to some extent since it is favorable in terms of its biocompatibility and fluid properties, it essentially has no effects against proliferation and activation of synovial cells. In addition, satisfactory therapeutic effects cannot be obtained with the use of zinc either.
Thus, the present invention provides a pharmaceutical composition, its production and its use that is able to effectively treat arthritic diseases by means of inhibiting proliferation and activation of synovial cells, which constitute the etiology of arthritic diseases such as rheumatoid arthritis, and particularly by suppressing matrix metalloproteinase.
As a result of conducting various studies to solve the above-mentioned problems, the inventors of the present invention found that, while hyaluronic acid (sodium salt) has essentially no inhibitory effects on proliferation and activation of synovial cells, and the inhibitory effects of zinc on proliferation and activation of synovial cells, and particularly on matrix metalloproteinases, are extremely low, a compound of hyaluronic acid and zinc surprisingly has extremely potent synovial cell proliferation inhibitory effects and matrix metalloproteinase suppression effects due to the synergistic effects namely a potentiating synergism interaction of both constituents, thereby leading to completion of the present invention.
Thus, the present invention provides an agent for treatment of arthritic disease containing a complex of hyaluronic acid and zinc.
The present invention also provides a matrix metalloproteinase MMP-9 suppresser containing a complex of hyaluronic acid and zinc.
The present invention also relates to the use of a complex of hyaluronic acid and zinc for production of an agent for treatment or arthritic disease.
Moreover, the present invention relates to the use of a complex of hyaluronic acid and zinc for the production of matrix metalloproteinase MMP-9 suppresser.
Moreover, the present invention discloses a treatment method for arthritic disease comprising the administration of a complex of hyaluronic acid and zinc to a patient having an arthritic disease.
Finally, the present invention discloses a method for suppressing accelerated production of matrix metalloproteinase MMP-9 comprising the administration of a complex of hyaluronic acid and zinc to a patient having accelerated production of matrix metalloproteinase MMP-9.